An increased understanding of the mechanisms by which T cells recognize virus and tumor-specific antigens has stimulated much interest in the use of specific T cells as adoptive immunotherapy for infections and malignant diseases. Cellular immunotherapy can be broadly defined as the administration of effector cells of the immune system for the treatment of disease. The primary function of the cellular immune system is to afford protection against pathogens, including acute and persistent infections.
T cells recognize infected cells and prevent onset of disease by killing these target cells. However, the interplay of pathogens and the immune system is complex, as demonstrated by chronic infections developing in the presence of specific T cells, whereby the pathogens obviously could evade T-cell surveillance.
The ability of T cells to detect virtually any pathogenic invader is granted by its extraordinarily diverse receptor repertoire, which allows the T-cell pool to recognize a vast number of peptides upon presentation by major histocompatibility complex (MHC) molecules. Still, signaling through the T-cell receptor (TCR) (signal 1) is not sufficient for adequate T-cell activation, as costimulatory molecules provide indispensable signals for proliferation, survival, and differentiation (signal 2). In fact, naive T cells that only receive signal 1 without signal 2 are rendered anergic (unresponsive) or die through apoptosis. The integration of signals 1 and 2 is required for full T-cell activation, and the strength of these signals shapes the size of the ensuing T-cell pool. Moreover, full differentiation into effector T cells is generally dependent on a third signal, which is supplied by the antigen-presenting cell (APC) in soluble form and provides instructive signals for the type of effector T cell that is required. This ‘three-signal’ concept depicts a model for the activation of naive T cells and the subsequent formation of effector T cells. Yet, the immune system provides a plethora of diverse costimulatory molecules and these various types of signal 2 and 3 all contribute in their own unique manner to the quality of the T-cell response. Costimulatory signals and soluble forms of signal 3 can act on particular aspects of T-cell activation, such as survival, cell cycle progression, type of effector cell to be developed, and differentiation to either effector or memory cell.
It is now generally accepted that mature antigen-presenting dendritic cells (DCs) have to be “helped” by other lymphocytes, including CD4+ T cells, NK cells and NKT cells, in order to induce long-lived memory CD8+ T cells. This “help” induces the mature DCs to differentiate further, a process known as licensing. “Helper” signals has multiple effects on DCs, including the upregulation of costimulatory molecules, the secretion of cytokines, and the upregulation of several antiapoptotic molecules, all of which cumulatively potentiate the ability of DCs to optimally activate cognate T cells, especially CD8+ T cells. Moreover, “helper” lymphocytes may also express or secrete factors that directly affect T cell survival, cell cycle progression, type of effector cell to be developed, and differentiation to either effector or memory cell.
Persistent or chronic viral infections, such as HIV, HBV, or HCV, or the herpes viruses CMV and EBV, present a significant threat to society, and treatment options for infected individuals are in urgent demand. During viral persistence, the balance between the virus and the host immune response is crucial. The immune system keeps the virus in check, and the virus counters by evading the immune response to avoid clearance, ultimately tipping the balance in favor of the virus and causing disease in many cases. In most persistent viral infections, the continuous presence of the viral antigen renders virus-specific T cells to become dysfunctional.
During the past 20 years, human immunodeficiency virus (HIV) infection has become a pandemic, with more than 40 million people infected and already more than 20 million deaths from acquired immunodeficiency syndrome (AIDS). Data from exposed uninfected and from long-term nonprogressors strongly suggest that both HIV-specific CD8+ and CD4+ T-cell functions are essential for protective immunity. HIV-specific CD8(+) T cells persist in high frequencies in HIV-infected patients despite impaired CD4(+) T helper response to the virus, but, unlike other differentiated effector cytotoxic T lymphocytes, most continue to express the tumor necrosis factor receptor family member CD27. The ligand for CD27 (CD70) is also overexpressed in HIV-infected hosts and the nature of expression and potential functional consequences of CD27 expression on HIV-specific CD8(+) T cells is therefore of interest. Analysis of CD27(+) and CD27(−) T cells derived from the same HIV-specific clone has revealed that retention of CD27 do not interfere with acquisition of effector functions, and that after T cell receptor stimulation, CD27(+) cells that concurrently are triggered via CD27 exhibit more resistance to apoptosis, interleukin 2 production, and proliferation than CD27(−) T cells. After transfer back into an HIV-infected patient, autologous HIV-specific CD27(−) T cells rapidly disappear, but CD27(+) T cells derived from the same clone persist at high frequency. It is therefore suggested that the CD27-CD70 interaction in HIV infection may provide CD27(+) CD8(+) T cells with a survival advantage and compensate for limiting or absent CD4(+) T help to maintain the CD8 response. (Ochsenbein et al., Exp Med. 2004 Dec. 6; 200(11):1407-17)
Similar to HIV, it has been found that also patients infected with persistent viral infections other than HIV have a subset of intermediate functional effector-memory T cells not fully differentiated but express not only CD28 but also CD27. It has been shown that these cells have a higher proliferative capacity than mature CD8+ T cells which are devoid of both CD28 and CD27. (Decrion et al., Immunology, 121, 405-415, 2007).
Thus, there is a strong correlation between the potency and specificity of the virus-specific CTL response and the magnitude of the viral load and the clinical outcome in most individuals infected with a chronic viral disease, the delay or arrest in disease progression in long-term nonprogressors, and the protection of some virus-exposed individuals from infection. It is likely that increasing the quality and breadth of the virus-specific CTL response would augment the control of virus replication in chronically infected individuals and either stabilize or improve their clinical course.
One strategy for fighting viral infections and increase the CTL response would therefore be adoptive T-cell therapy, which involves the transfer of effector T cells to restore specific T-cell responses in the host. Adoptive cell transfer therapy is the administration of ex vivo activated and expanded autologous virus-reactive T cells.
In present methods of adoptive immunotherapy of HIV patients problems with decline of transferred CTLs are pronounced. Although the decline in transferred CTLs in peripheral blood in part reflects migration to lymph node sites, the loss of antiviral activity over time indicates the CTLs die or are rendered dysfunctional at these local sites of HIV replication. Strategies to provide help to transferred CD8+ CTLs should improve CTL survival and elucidate the therapeutic potential of CTLs for controlling progression of HIV infection and also other viral infections.
Consequently, there is a need for an improved method of preparing a T cell population for use in adoptive immunotherapy against viral infections that increases proliferation and survival of antigen-specific T cells during their activation.